Mental health literacy had a transient effect on depressive symptoms. Other
than this, none of the interventions significantly reduced symptoms relative
to their comparator at 6 weeks or subsequently. Neither folic acid plus
B12 nor physical activity were effective in reducing depressive
symptoms.

Depression in later life is common with 3.6–4.8% of people over 60
years reporting 12-month major depression, and 8–37.4% report
significant depressive
symptoms.1,2
Late-life depression may result in impaired cognitive, physical and social
functioning, and predisposes to
suicide.3,4
It is estimated that by 2020 depressive disorders will be the second highest
cause of disease
burden,5 and the
prevalence of depressive disorders is projected to double from its present
level by 2050.1 In
order to minimise the adverse impact of depression, effective, economical and
accessible prevention strategies that are scalable to a community-wide level
clearly need to be developed. Ideally, these should also build upon the
community’s preference for lifestyle and psychological interventions to
maximise adherence.6
With the aim of developing effective preventive strategies, the first step is
to identify interventions that reduce depressive symptoms in
community-dwelling individuals. If successful, such interventions constitute
the basis for larger indicated prevention
trials.7 To date,
however, the development and evaluation of such programmes has been
minimal.

We identified three candidate interventions with potential utility for
prevention in older people. Physical activity has been shown in some studies
to be an effective treatment in mild to severe depression, with remission
rates comparable with cognitive therapy or antidepressant
medication.8,9
Mediated physical activity programmes (e.g. interventions that are delivered
entirely by the telephone, mail or the internet) may increase physical
activity levels, suggesting a potential role for these non-intensive methods
in large-scale preventive
initiatives.10 Some
programmes that improve mental health literacy have been found to reduce
depression symptoms in a number of
trials,11,12
whereas others have found improved depression literacy but no change in
depressive
symptoms.13 There
are indications from clinical and treatment studies that folate and vitamin
B12 may reduce or prevent
depression.14,15
Folic acid and vitamin B12 supplementation may prevent depression
by lowering homocysteine levels, which are elevated in individuals with
depression and in some samples of older
people.16 Low
folate levels and vitamin B12 have been found in community samples
of adults with
depression16
although the evidence is uncertain whether folate and vitamin B12
offer effective treatment for
depression.17
Supplementary folic acid and vitamin B12 may reduce the long-term
risk of onset of depression via reduction of vascular and other metabolic risk
factors for late-life
depression.18

The present study investigated the effectiveness of promoting physical
activity, mental health literacy and combined folic acid and vitamin
B12 as preventive interventions for an older population with
elevated psychological distress. A factorial 2 (folic acid + vitamin
B12, placebo)×2 (physical activity promotion,
control)×2 (mental health literacy, control) design was chosen. This
design had the advantage of testing multiple inventions in a single trial and
incorporating appropriate control conditions for each intervention. Assuming
either no interaction or synergistic effects, factorial trials have the
potential to evaluate multiple interventions against appropriate control
conditions, effectively offering ‘three trials for the price of
one’.19
Further, healthcare significance may be enhanced because each intervention is
administered in the context of other interventions: there is evidence that
consumers try multiple, simultaneous approaches to address both physical and
mental health
problems.20 Pain
management materials served as the control for mental health literacy,
nutrition information for physical activity promotion, whereas a placebo
tablet was the control for folic acid + vitamin B12. Because of our
interest in developing an intervention that was genuinely scalable and
applicable in community settings, the trial was entirely delivered by either
telephone or mail with an emphasis on reducing the amount of person-to-person
contact both at screening and in the delivery of the programme. As a
consequence of this, we could not, and did not seek to formally diagnose
individuals with clinical depression. Highly distressed individuals (Kessler
Distress 10–Scale (K10) score of 30 or
greater)21 were
excluded as they were considered candidates for professional care rather than
preventive management. However, the trial did not exclude participants with
lower K10 scores who may have met clinical diagnostic criteria.

Participants

Participants were recruited from urban and rural sites by mail using
address and age (60–74 years) information provided by the Australian
Electoral Commission. These lists allowed representative population sampling
as voting is compulsory in Australia.

Selected participants had elevated psychological distress as assessed by
the K10 with scores 16 or greater (scores <16 indicate no or low levels of
psychological
distress);21 did
not engage in physical activity at public health recommended levels as
indicated by International Physical Activity Questionnaire (IPAQ)
scores;22 did not
take folic acid, vitamin B12 or vitamin B complex supplements; had
no history of dementia, bipolar disorder or current suicide risk; had
competent literacy skills; and did not have a medical condition that would
contraindicate exercise or folic acid use. Individuals with high likelihood of
a depressive disorder with K10 scores of 30 or
greater23 were
excluded. Those with low levels of red cell folate (<250 nmol/l) and
vitamin B12 (<130 nmol/l), and abnormal thyroid-stimulating
hormone levels (0.35–5.0 mu/l) were excluded as participation may have
lead to potential adverse outcomes. Folate and vitamin B12
deficiency can lead to anaemia, fatigue, neurological degeneration, weight
loss, red and painful tongue and heart
palpitations.24
Thus it was unethical to recruit individuals with a medical need for
supplementation.

Recruitment occurred between 22 October 2005 and 4 September 2006 with the
24-month intervention and data collection occurring from 4 January 2006 to 18
September 2008. Human research ethics committees at the Australian National
University, Australian Capital Territory Health Department and the University
of Sydney, Australia, approved the study. All participants provided written
informed consent.

Interventions

Eligible participants were enrolled into an intervention programme that was
delivered over 24 months in ten modules. All interventions involved five brief
telephone tracking calls over the first 5 weeks and five more telephone calls
at 4, 8, 13, 18 and 22 months, in order to motivate participants to read the
material, facilitate their engagement with the project and material, and
ensure that the material and related tasks have been understood – no
supportive counselling was given. With the exception of the folic acid +
vitamin B12 and placebo tablets, all interventions involved five
modules of information delivered by mail in Weeks 1–5, followed by a
further five modules sent out at 4, 8, 13, 18 and 22 months.

Mental health literacy arm

Mental health literacy. Modules 1–5 were contained in a
depression literacy manual
(www.beyondblue.org.au)
including information regarding: prevalence and depressive symptoms; barriers
to help-seeking such as stigma; prevention; the evidence for medical,
psychological and alternative treatments; and resources for support and
treatment of
depression.25 The
additional mental health literacy modules were booklets that addressed sleep,
anxiety disorders and their treatment, structured problem-solving training,
cognitive–behavioural strategies for depression and interpersonal
therapy. These were developed by the Centre for Mental Health Research,
Australian National University.

Dietary supplementation arm

Folic acid + vitamin B12tablets. These
were formulated as a daily oral dose of one tablet consisting of folic acid
400 mcg and vitamin B12 100 mcg (Matchland Pty Ltd, t/a New
Products Development –ABN57052101176, Brisbane, Australia). The folic
acid dose of 400 mcg/d was selected as it has been shown to be associated with
90% of the maximal decrease in plasma homocysteine concentration for older
adults.27 Following
a safety review subsequent to a widely reported publication on the association
between folate and colorectal
adenomas,28 the
protocol changed to two daily oral doses (folic acid 200 mcg and 50 mcg each)
from July 2007 to minimise unmetabolised folic acid in the blood. Also as a
consequence of the publicity given to a study reporting a possible link
between folic acid and colon
cancer,28 26
participants withdrew from the study, and 72 participants stopped taking the
tablets because of concerns relating to the information we provided regarding
safety and the changes in the protocol for administrating the tablets.
Adherence was monitored by telephone assessments (6 weeks, 6, 12 and 24
months) and ten brief telephone calls (1–5 weeks, and 4, 8, 13, 18 and
22 months) during which participants were requested to count the left over
tablets and also by measurement of blood assay at baseline, 12- and 24-month
assessments.

Placebo. Placebo tablets were manufactured by the same producers of
the folic acid + vitamin B12 tablets and were identical except for
the omission of the active substances under investigation.

Physical activity promotion arm

Physical activity promotion. This included a printed manual that was
a targeted intervention based on the participant’s stage of
change,29 and a
pedometer (Digi-Walker SW-700, Yamax Inc, Tokyo,
Japan).30 The
manual’s content was informed by social cognitive theory and the
transtheoretical
model,31 and
contained evidence-based strategies to promote greater physical activity
levels. Five newsletters including information on physical activity and local
resources were delivered at 4, 8, 13, 18 and 22 months.

Nutrition promotion. This consisted of an evidence-based nutrition
manual32 on the
dietary requirements of older adults (modules 1–5). Modules 6–10
included additional information and strategies to promote positive eating
habits.

Measures

Demographic, physical and mental health

Age, gender, years of education, marital and employment status were
ascertained. A checklist identified vascular disease and other health
problems,33 and
side-effects potentially associated with folic acid + B12
supplementation were monitored with a modified version of the Liverpool
University Neuroleptic Side Effect Rating
Scale.34 The K10
was selected as a screening tool to identify individuals with elevated
psychological distress (anxiety and depression) because of its brevity and
community use.35 A
modified version of the Level of Contact Report examined exposure to
depression.36 This
survey lists 12 situations in which intimacy of contact with severe mental
illness varies.

Outcome measures

Depressive symptoms and physical activity outcomes were assessed at
baseline, 6 weeks (within 1 week of this time frame), 6, 12 and 24 (all within
2 weeks of this time frame).

Depressive symptoms. The Patient Health Questionnaire (PHQ–9)
is a diagnostic tool specific to
depression,37,38
and hence was used as the primary outcome measure.

Physicalactivity. The International Physical Activity
Questionnaire – Short Form
(IPAQ–SF)22
was used as a self-report measure of physical activity.

Sample size and power

Power calculations led to an initial target sample size of 2000. This would
have enabled the detection of main effects of each intervention of 0.125
standard deviations with 80% power with α = 0.05 assuming a
pre–post-test correlation of 0.50. This sample size would also have
given reasonable power to detect interactions between interventions. The rate
of recruitment of participants meeting inclusion criteria prompted
reconsideration of the target sample size. A final target of 1000 participants
maintained power above 80% to detect main effects of 0.18 standard deviations,
a value below the size of small effects. Although the power to detect
interactions was compromised, the primary interest of the study lay in the
effectiveness of each intervention rather than questions of synergies. From a
total of 24 352 surveys received and screened, 909 participants met the study
criteria and were randomised into one of eight intervention arms
(Fig. 1).

Completers, participants completing the survey for that time point;
non-completers, participants that did not complete the assessment at that time
point but continued with the study and were assessed at the following time
point; n/a, not applicable.

Randomisation

Randomisation followed the screening assessment with block size fixed at
eight and using strata comprising location, gender and high (19) and low
(16–18) K1021
depression scores (conducted by A.J.M.) using an automated computerised
system. Further, the internet site
random.org was
used (conducted by J.G.W.) to randomly allocate a label ‘A’ or ‘
B’ to the folic acid + vitamin B12, and placebo tablet
bottles to ensure concealment of their content. Participants, interviewers,
investigators and the survey administrators were masked to active intervention
and folic placebo allocation. One participant was unmasked at 15 months
because of impending medical treatment unrelated to the study. Participants
were masked regarding the mental health literacy intervention and physical
activity promotion as all of the intervention arms were delivered as a healthy
ageing programme.

Statistical methods

Mixed-model repeated measures analysis of variance (MMRM) was used to
evaluate hypotheses concerning differential change between each active
intervention and its comparator. Within-person variation was modelled using an
unstructured covariance matrix. Degrees of freedom were estimated using
Satterthwaite’s
approximation.39
Initial models included effects of each intervention arm and interaction
between interventions. Final models only included tests for main effects as
all interactions between the three interventions were not significant. As
baseline data were complete, no imputation of baseline missing data was
necessary. Mixed models yield an intention-to-treat analysis, using all
available measurement points for each participant under the assumption that
withdrawal data are missing at random. Version 15 of SPSS for Windows was used
for all statistical analyses.

Estimated population marginal means for the model shown in
Table 2 are plotted in Fig. 2.
Error bars represent standard error of the mean.

More comprehensive models were also examined, controlling for the effects
of age, gender, years of education, marital status, employment status, count
of medical conditions, history of vascular conditions, mental illness exposure
and K10 distress score at screening. These models yielded similar results.
Most importantly, the significant effect for the mental health literacy
intervention at 6 weeks was maintained after controlling for these potential
confounders (t(865) = –2.43, P = 0.015). We also
undertook a secondary analysis excluding individuals with high K10 scores
(i.e. >24); the same findings resulted.

Safety and adverse events

There were no significant adverse events related directly to the study.
Thyroid, liver and kidney function, haematological parameters, vitamin
B12 and red cell folate levels were assessed by Capital Pathology
(part of Sonic Health Care Ltd) at baseline, 12 and 24 months. At the 24-month
assessment, two participants required urgent follow-up treatment (unrelated to
their participation in the randomised controlled trial (RCT) from their
nominated healthcare provider due to markedly elevated
gamma-glutamyltransferase (γ-GT) (1350 u/l) and thyroid-stimulating
hormone (198.0 mu/l) levels, respectively. There were no differences in
self-reported adverse events between the folic acid + B12
intervention and placebo groups at baseline or follow-up assessments, except
at 6 weeks when placebo participants reported significantly more side-effects
than folate participants (F(1,898) = 4.58, P = 0.033).
Nineteen participants withdrew from the intervention citing ill health. Two
participants died during the 24-month period with both receiving the placebo
tablet. Fifteen participants required further assessment and monitoring for
potential suicidality; however, no participants withdrew because of
depression.

Discussion

Main findings

In this study of symptomatic community-dwelling participants, none of the
interventions as planned, i.e. mental health literacy, folic acid + vitamin
B12 supplementation and promoting physical activity, were effective
in reducing depressive symptoms relative to their comparators at 24 months.
Post hoc analyses indicated that only those who received the mental
health literacy intervention experienced a significant decrease in depressive
symptoms at 6 weeks relative to the control condition (d = 0.15, with
control for covariates). This finding may indicate that promoting mental
health literacy is effective in the short term. However, this effect may be
due to a type 1 error since the effect was brief and the magnitude small.
Moreover, we are reluctant to weigh it too strongly given that our analysis
was post hoc. Interestingly, a recent meta-analysis reported that
passive education (or mental health literacy) can produce significant effects
on depression symptoms suggesting replication is
critical.12

An important outcome of the study was the failure to detect any effect of
folic acid (400 mcg/d) + B12 (100 mcg/d) supplementation on
reduction of depressive symptoms. This was unlikely to be as a result of
adherence issues given that the biochemical analyses showed large increases in
blood levels of folate and vitamin B12 in those receiving the
active tablet. This finding does not preclude an effect at higher doses than
used in this trial. Although the doses of folic acid and vitamin
B12 used in our study prevented further increase in homocysteine
(as occurred in the placebo group) they appear to have been insufficient to
lower homocysteine levels relative to baseline. Recent studies in the elderly
(>70 years) suggest that >600 mcg/d vitamin B12 may be
required to reduce homocysteine and methylmalonic
acid.40 We
therefore cannot exclude the possibility that the vitamin B12 dose
was too low for adequate bioefficacy even though it was 42 times greater than
the Australian recommended dietary
intake.41 Use of
higher folic acid doses was not possible because of ethical concerns relating
to heightened colorectal cancer risk in otherwise asymptomatic elderly
people.28

Randomised controlled trials have investigated a range of folate doses from
200 to 5000 mcg/day with varying
findings.17,18
Folic acid and vitamin B12 are unlikely to be an effective
short-term intervention for preventing depression in doses that can be
recommended as a dietary supplement. The study replicates the null effect from
an earlier, smaller and thus underpowered
trial.14 It is
possible that such interventions need to be delivered over a longer period to
reduce vascular and other metabolic risk factors to
depression.42

The intervention to promote physical activity did not do so to a greater
extent than the comparator invention. As a consequence, the hypothesis that
physical activity would reduce depressive symptoms was not comprehensively
tested. We cannot rule out the possibility that a different programme might
have successfully promoted physical activity. However, our programme was
rigorous and a good exemplar of a public health approach to promoting physical
activity: it was developed in conjunction with consumer input and
consideration of the current evidence base, especially for mediated delivery
of physical activity
interventions,10
suggesting that significant changes would be needed for this approach to be
effective. Similarly, a more intensive programme might be preventive, but this
casts doubt on the likelihood of achieving this without substantial individual
attention thus precluding widespread use.

All trial and control interventions were associated with a reduction in
depressive symptoms (Cohen’s d = 0.32, F(4, 833.4) =
37.00, P<0.001) over 24 months. It is difficult to determine
whether this reflected the course of depression over time, regression to the
mean,43 a
non-specific effect of contact with the trial
team11 or because
of engagement in community activities. Because trials without strong team
support show similar
trajectories,44 it
is unlikely to be as a result of the impact of the telephone interviewers even
though 43% of the participants responded that the telephone contact with
interviewers was an important component of the intervention and 90% reported
that the telephone interviews were needed to remain engaged with the
study.

Based on screening cut-off scores provided by the K10, we know that most of
the participants (i.e. 91%) were at low to medium
risk45 of having a
depressive or anxiety disorder at the time of screening (K10 scores
16–30). We judged that 58% of participants had a low probability (3% or
less) of meeting DSM–IV criteria for an affective
disorder.21,23
Ideally, trials should incorporate telephone-based diagnosis to identify those
meeting criteria for a depressive disorder. However, this will often be
incompatible with the sample sizes required to detect preventive effects.

There is a difficulty characterising our results as evidence of either
treatment or prevention of a depressive disorder. Our main finding that
participants in the mental health literacy intervention experienced a
significant decrease in depressive symptoms at 6 weeks relative to the control
condition is subject to a difficult nosological
issue.46 It could
be argued that the Beyond Ageing Project is a treatment RCT as mental health
literacy resulted in a short-term reduction in depressive symptoms compared
with the control. However, the study can be appropriately defined as a
prevention trial given that depression prevention programmes may target
numerous risk factors including high levels of psychological
distress.47

Strengths and limitations

This is one of the largest trials to date to examine the effectiveness of
psychological- and lifestyle-based preventive interventions for a high-risk
group of community-dwelling older adults with psychological distress. The
study was well executed and participants were engaged. The interventions
chosen were acceptable, safe, low cost and accessible. The drop-out rate from
randomisation to the 24-month assessment of 13.5% (82.7% of participants
randomised into the RCT completed the 2-year intervention) was remarkably low
relative to other psychosocial and lifestyle-based intervention trials for
depression that report drop-out rates of
10–23%,9,14
with all except
one14 involving
brief interventions with less than 3 months duration. Unlike many studies
executed in clinical settings, the present study delivered the interventions
in a real-world setting despite stringent exclusion criteria due to ethical
considerations.

The study had the limitation, however, that of the 24 352 older adults who
returned their surveys, only 909 (3.8%) met the criteria or agreed to
participate in the intervention. Although this may appear to be a low
recruitment rate, the trial was unique in attempting to ascertain participants
from a defined population sampling frame. This approach necessarily targets a
large number of individuals who ultimately do not qualify for inclusion.
However, bypassing conventional means of recruitment such as advertising and
actively, and individually, soliciting participants is likely to have resulted
in the inclusion of individuals who may not have recognised their at-risk
status or been reluctant to seek assistance from healthcare professionals.

In the development of the trial, it was difficult to determine whether our
original sample size target would be achieved given that few community-based
interventions of this scale have been conducted. We anticipated recruiting
2000 people based on prevalence rates for this age group and on our experience
of previous recruitment rates for community samples. However, there were
issues that impinged on our trial that made the participation rate lower than
expected. For example, many participants may have been unable to commit to a
2-year programme. Our target group was older than previous trials and may have
been reluctant to engage in scientific research. Also, we suspect that this
group may have overestimated their activity levels, which resulted in many
potential participants meeting exclusion criteria. Although the targeted
recruitment rate was not met, the achieved sample would have detected small
effects (down to approximately 0.2 standard deviations) under the original
assumptions. It is possible that negative interactions may have reduced the
efficiency of the trial but, in the absence of evidence of effects of
individual interventions this is not likely to explain the failure to detect
any benefit of exercise or folic acid and B12 supplementation.

Implications

None of the interventions were effective in reducing depressive symptoms at
24 months compared with their respective comparators. However, our study
suggests that there may be a role for brief mental health literacy
interventions in reducing depressive symptoms, at least over short periods of
time. Mental health literacy interventions are inexpensive and their indicated
preventive effect may be worthwhile if provided to large numbers of older
community-dwelling people with distress and, particularly, if the resultant
literacy could be harnessed to encourage subsequent evidence-based treatment.
Further investigation is needed to determine the appropriate
dose–response levels of folic acid and vitamin B12
supplementation, if there are indeed any, for managing depressive symptoms in
older adults. However, the prospect of using these dietary supplements at
acceptable dosages as a preventive strategy for older people with
psychological distress seems limited.

Funding

This study was supported by beyondblue: the national
depression initiative and the Australian
Government Department of Health and Ageing. H.C. is supported
by NHMRC Fellowship 525411. J.G.W. is supported
by NHMRC Capacity Building Grant
418020.

Acknowledgments

We gratefully acknowledge: Elizabeth Parkes and the telephone interviewing
team; research assistance from Amanda George; administrative support from
Dimity Crisp, Kim Pullen, Trish Jacomb and Karen Maxwell; research design
input from Kaarin Anstey, Kathy Griffiths, and Marjan Kljakovic; and medical
support from Marjan Kljakovic.

Social Psychiatry Research Unit. The Canberra Interview for the
Elderly (CIE): a new field instrument for the diagnosis of dementia and
depression by ICD–10 and DSMIII–R. Acta Psychiatr
Scand1992; 85: 105–
13.

Australian Government National Health and Medical Research Council,
New Zealand Ministry of Health. National Reference Values for
Australia and New Zealand: Vitamin B12.
Australian Government National Health and Medical Research Council, 2008
.